Our main accomplishments during the previous funding cycle relevant to the present application are: 1. Identification of new endocannabinoid (EC)-like compounds in the central nervous system, their synthesis and evaluation in various biological settings; 2. Characterization of a neuroprotective role for the EC system in traumatic brain injury (TBI). 3. Defining a role for the EC system in the regulation of skeletal metabolism. Based on our findings we hypothesize that the ECs, EC-like compounds and the cannabinoid receptors have differential and distinct pathophysiologic roles, both after TBI and in maintaining bone remodeling at balance. We propose to test this hypothesis using an array of newly synthesized EC-like compounds (i.e., fatty acid ethanolamides, fatty acid glyceryl esters and fatty acid amides), test their binding to cannabinoid receptors and define their pharmacological actions (by Dr. Mechoulam). This will be followed by identification of corresponding endogenous materials in the brain (by Dr. Mechoulam) and testing their effects in a mouse model for TBI and their role in neurogenesis (by Dr. Shohami) and on the skeleton (by Dr. Bab). These compounds will be also assessed in other biological models available to the PPG such as Dr. Martin's models for pain and reward (Project 1). To further map the role of EC system components in post-TBI recovery and bone remodeling we will analyze TBI-triggered processes (Dr. Shohami) and bone metabolism (Dr. Bab) in mice with conditional deletion of EC genes in the brain and in the skeleton. Some of these mice will be generated by Dr. Cravatt (Project 3) or provided by our collaborators Dr. Zimmer and Dr. Lutz. In a complementary strategy, we will test the post-TBI and skeletal effects of inhibitors of enzymes involved in EC synthesis and degradation (from Drs. Razdan and Cravatt) and of cannabinoid receptor agonists and antagonists (from Drs. Razdan and Mechoulam). Mapping the activity of the EC-like compounds and each of the EC system components is proposed with the objective of identifying molecular drug targets for the benefit of TBI victims, patients with neurodegenerative diseases and sufferers of skeletal deficits resulting from trauma and osteoporosis. Such mapping will probably contribute to the general understanding of the EC system and hence, drug dependence.